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Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features.

ABSTRACT: We report an 8-month-old infant with decreased consciousness after a febrile episode and reduced oral intake. He was profoundly acidotic but his lactate was normal. Serum triglycerides were markedly elevated and HDL cholesterol was very low. The urine organic acid analysis during the acute episode revealed a complex pattern of relative hypoketotic dicarboxylic aciduria, suggestive of a potential fatty acid oxidation disorder. MRI showed extensive brain abnormalities concerning for a primary energy deficiency. Whole exome sequencing revealed heterozygotic HMGCS2 variants. HMGCS2 encodes mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 (HMGCS2), which catalyzes the irreversible and rate-limiting reaction of ketogenesis in the mitochondrial matrix. Autosomal recessive HMG-CoA synthase deficiency (HMGCS2D) is characterized by hypoketotic hypoglycemia, vomiting, lethargy, and hepatomegaly after periods of prolonged fasting or illness. A retrospective analysis of the urine organic acid analysis identified 4-hydrox-6-methyl-2-pyrone, a recently reported putative biomarker of HMGCS2D. There was also a relative elevation of plasma acetylcarnitine as previously reported in one case. Our patient highlights a unique presentation of HMGCS2D caused by novel variants in HMGCS2. This is the first report of HMGCS2D with a significantly elevated triglyceride level and decreased HDL cholesterol level at presentation. Given this, we suggest that HMGCS2D should be considered in the differential diagnosis when hypertriglyceridemia, or low HDL cholesterol levels are seen in a child who presents with acidosis, mild ketosis, and mental status changes after illness or prolonged fasting. Although HMGCS2D is a rare disorder with nonspecific symptoms, with the advent of next-generation sequencing, and the recognition of novel biochemical biomarkers, the incidence of this condition may become better understood.

SUBMITTER: Conboy E

PROVIDER: S-EPMC6122033 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features.

Conboy Erin E Vairo Filippo F Schultz Matthew M Agre Katherine K Ridsdale Ross R Deyle David D Oglesbee Devin D Gavrilov Dimitar D Klee Eric W EW Lanpher Brendan B

JIMD reports 20171014

We report an 8-month-old infant with decreased consciousness after a febrile episode and reduced oral intake. He was profoundly acidotic but his lactate was normal. Serum triglycerides were markedly elevated and HDL cholesterol was very low. The urine organic acid analysis during the acute episode revealed a complex pattern of relative hypoketotic dicarboxylic aciduria, suggestive of a potential fatty acid oxidation disorder. MRI showed extensive brain abnormalities concerning for a primary ener ...[more]

PMID: 29030856

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Project description:Background: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare autosomal recessive metabolic disorder caused by mutations of the HMGCS2 gene. To date, no more than 60 patients have been reported throughout the world. Purpose: To analyze the clinical, biochemical, molecular, and outcome features of HMGCS2D in a case series of 10 new Chinese patients. Methods: This retrospective study includes 10 Chinese patients diagnosed with HMGCS2D. We collected and analyzed clinical data for all patients. We also reviewed clinical data for 39 cases that had been reported previously. Results: All of our patients had experienced their first metabolic crisis before 12 months old. The most common clinical manifestations were anorexia, dyspnea, and disturbance of consciousness (10/10), followed by vomiting (8/10), fever (7/10), cough (4/10), diarrhea, and seizures (3/10). Each patient (10/10) had a different degree of hepatomegaly and increased aminotransferase, severe metabolic acidosis, and hypofibrinogenemia. 9 patients presented with severe hypoglycemia and weak positives on qualitative tests of urinary ketone body. Patient 3 was the only one without hypoglycemia. Five patients had hypocalcemia, five patients had hyperammonemia, four patients had hyperuricemia, and three had hypertriglyceridemia. During the metabolic acidosis episode, we observed high dicarboxylic acid values in urine, and the elevated ratio of blood acetylcarnitine to free carnitine may have been an additional biochemical signature. However, all returned to normal during the interictal interval. Molecular analysis identified 15 variants in the HMGCS2 gene, of which 10 were novel (c.220G>A/p.E74K, c.407A>G/p.D136G, c.422T>A/p.V141D, c.719A>C/p.D240A, c.821G>A/p.R274H, c.39dupA/p.L14Tfs*59, c.1394delA/p.N465Tfs*10, c.788delT/p.L263Cfs*36, c.717T>G/p.Y239*, and c.1017-2A>G). Combining these with previous cases, the known mutation c.1201G>T/p.E401* has been found in 6/40 (15.0%) of mutated alleles in 21 Chinese patients from 20 families, while none have been found in other populations. We found that patients with biallelic truncation mutation appeared to show a more severe clinical condition through a literature review. Conclusion: This study analyzed the phenotypic and genetic features of HMGCS2D in a Chinese case series. We also expanded the HMGCS2 mutational spectrum with 10 novel variants. The c.1201G>T/p.E401* mutation was the most frequent, representing 15.0% of the mutated alleles in reported unrelated Chinese patients, and thus, it may be a hot spot mutation.

Project description:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG Co-A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20-month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4-hydroxy-6-methyl-2-pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3-hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the HMGCS2 gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge.

Dataset Information

Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features.

Publications

Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features.

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